The present invention relates to a novel pharmaceutical composition suitable for treating peptic ulcers and erosions, and other gastrointestinal ailments associated with gastric hyperacidity. More particularly, this invention pertains to an orally administered, pharmaceutical composition comprised of the histamine H.sub.2 -receptor antagonist cimetidine and the antimuscarinic agent pirenzepine, and a method of using such a pharmaceutical composition to treat gastrointestinal dysfunctions.
It has been recognized that peptic ulcers and erosions can be treated with antimuscarinics, such as atropine, which inhibit the secretion of acid into the stomach. However, the effectiveness of such drugs has been limited by the significant side effects, e.g. increased heart rate, and depressed salivation, which occur at the therapeuttic dosage level.
More recently, it has been observed that selective histamine H.sub.2 -receptor antagonist, such as cimetidine, and ranitidine, can be used in the treatment of conditions where there is a hypersecretion of gastric acid. These antagonists are distinguished from the drugs commonly known as "antihistamines", e.g. mepyramine, which selectively block the H.sub.1 -receptors of histamine to inhibit stimulation of the smooth bronchial and other muscles. See, Black et al. (Nature 1972, 236, 385); and Ash and Schild (Brit. J. Pharmacol. Chemother, 1966, 27, 427).
A marked improvement in the healing of peptic ulcers and erosions has been noticed based on the use of the H.sub.2 -receptor blockers. More recently, the introduction of 24 hour pH-metry has enabled quantitative diagnostic and prophylatic information to be reliably gathered in a short time. Such techniques have demonstrated that the therapeutic effect of the H.sub.2 -receptor antagonist is related to an increase in luminal gastric pH, particularly between about 11:00 p.m. and 6:00 a.m.
However, the H.sub.2 -receptor blockers such as cimetidine have also been associated with certain undesirable side effects, including diarrhea and dizziness. Additionally, it is now known that even the continuous 24 hour infusion of high doses of H.sub.2 -receptor blockers will not induce a continuous 24 hour anacidity or near-neutral pH values in the stomach. Therefore, because it has been demonstrated that blockage of the histamine H.sub.2 -receptors alone is not effective to eliminate gastric acidity, it has been suggested that the proton secretion associated with peptic ulcers is also induced by factors other than H.sub.2 -receptor stimulation.
Thus, it would be desirable to provide a pharmaceutical composition for inhibiting the various mechanisms for proton secretion by which gastric hyperacidity results, and which could be administered with reduced undesirable side effects.
At times, particularly in the treatment of the gastric hyperacidity associated with Zollinger-Ellison syndrome, conventional doses of antimuscarinics and H.sub.2 -receptor antagonists have been given separately to the same patient at the same time. Additionally, Londong et al. reported in Scand. J. Gastroent. 15 (Suppl. 66): 103 (1980) that the combined intravenous injection of the antimuscarinic pirenzepine and the H.sub.2 -receptor antagonist cimetidine suppressed stimulated acid secretion more than either drug alone. The combined injection was reportedly accompanied by such side effects as blurred vision, dry mouth and weariness.
However, there has been no recognition that the antimuscarinic agent pirenzepine and the H.sub.2 -receptor antagonist cimetidine should be combined in a single oral formulation for effectively treating peptic ulcers and other gastrointestinal diseases, at lower effective dosages than the dosages at which the separate drug components are conventionally administered, with prolonged therapeutic effect and reduced side effects.
Accordingly, it is an object of the invention to provide an orally administered pharmaceutical composition containing the H.sub.2 -receptor antagonist cimetidine and the antimuscarinic pirenzepine, which can be used to effectively treat peptic ulcers and the other gastrointestinal conditions associated with hyperacidity, at lower dosages and with less side effects than are associated with the conventional administration of the separate drug components.
Still another object of this invention is the provision of a method for treating peptic ulcers and other gastrointestinal conditions associated with hyperacidity, by orally administering a pharmaceutical composition containing both the H.sub.2 -receptor antagonist cimetidine and the antimuscarinic agent pirenzepine.
These objects and other advantages of the invention will be apparent from the detailed description which follows.